Effect of Leptin Receptor Q223R Polymorphism on Clostridioides difficile Infection-Induced Macrophage Migration Inhibitory Factor Production.

Proinflammatory cytokine levels and host genetic makeup are key determinants of Clostridioides difficile infection (CDI) outcomes. We previously reported that blocking the inflammatory cytokine macrophage migration inhibitory factor (MIF) ameliorates CDI. Here, we determined kinetics of MIF production and its association with a common genetic variant in leptin receptor (LEPR) using blood from patients with CDI. We found highest plasma MIF early after C difficile exposure and in individuals who express mutant/derived LEPR. Our data suggest that early-phase CDI provides a possible window of opportunity in which MIF targeting, potentially in combination with LEPR genotype, could have therapeutic utility.

Prevalence of SARS-CoV-2 Infection among Children and Adults in 15 US Communities, 2021

During January-August 2021, the Community Prevalence of SARS-CoV-2 Study used time/location sampling to recruit a cross-sectional, population-based cohort to estimate SARS-CoV-2 seroprevalence and nasal swab sample PCR positivity across 15 US communities. Survey-weighted estimates of SARS-CoV-2 infection and vaccine willingness among participants at each site were compared within demographic groups by using linear regression models with inverse variance weighting. Among 22,284 persons >2 months of age and older, median prevalence of infection (prior, active, or both) was 12.9% across sites and similar across age groups. Within each site, average prevalence of infection was 3 percentage points higher for Black than White persons and average vaccine willingness was 10 percentage points lower for Black than White persons and 7 percentage points lower for Black persons than for persons in other racial groups. The higher prevalence of SARS-CoV-2 infection among groups with lower vaccine willingness highlights the disparate effect of COVID-19 and its complications.

Clinical utility of multiplex PCR in the detection of pathogens from sterile body fluids.

Rapid identification of pathogens in normally sterile body fluid (NSBF) is essential for appropriate patient management, specifically antimicrobial therapy. Limited sensitivity and increased time to detection of traditional culture prompted us to evaluate additional testing to contribute to the diagnosis of infection. The purpose of this study was to evaluate the GenMark Dx ePlex Blood Culture Identification (BCID) Panels on positive body fluids inoculated into blood culture bottles for the detection of microorganisms. A total of 88 positive body fluids from blood culture bottles were analyzed using a Gram-Positive, Gram-Negative, and/or Fungal pathogen BCID Panel based on the Gram stain result. Each result was compared to routine culture performed from the positive bottle. When using culture as a reference standard, we found the ePlex multiplex panel performed with a positive percent agreement of 96.5% and a negative percent agreement of 99.8%. The use of multiplex PCR may be a useful supplement to routine culture for NSBF in blood culture bottles. IMPORTANCE: The identification of pathogens in normally sterile body fluid (NSBF) is performed using routine culture, the current gold standard. Limitations of this method include sensitivity and increased turnaround times which could potentially delay vital patient care, especially antimicrobial therapy. Adaptations of NSBF in blood culture bottles prompted us to consider the utility of additional methods to bridge the gap in diagnostic challenges for these life-threatening infections. Multiplex molecular panels have been manufactured for use with multiple specimen types including blood, cerebral spinal fluid, stool, and respiratory. Therefore, the purpose of this study was to evaluate the off-label use of ePlex Blood Culture Identification Panels on positive body fluids grown in blood culture bottles for the detection of microorganisms for research purposes.

Clock-talk: have we forgotten about geographic variation?

Wyeomyia smithii, the pitcher-plant mosquito, has evolved from south to north and from low to high elevations in eastern North America. Along this seasonal gradient, critical photoperiod has increased while apparent involvement of the circadian clock has declined in concert with the evolutionary divergence of populations. Response to classical experiments used to test for a circadian basis of photoperiodism varies as much within and among populations of W. smithii as have been found in the majority of all other insects and mites. The micro-evolutionary processes revealed within and among populations of W. smithii, programmed by a complex underlying genetic architecture, illustrate a gateway to the macro-evolutionary divergence of biological timing among species and higher taxa in general.

Induction of a cytokine storm involves suppression of the Osteopontin-dependent TH1 response.

Cytokine release syndromes represent a severe turn in certain disease states, which may be caused by several infections, including those with the virus SARS-CoV-2. This inefficient, even harmful, immune response has been associated with a broad release of chemokines. Although a cellular (type I) immune reaction is efficacious against viral infections, we noted a type I deficit in the cytokine patterns produced by cytokine storms of all reported etiologies. Agents including lipopolysaccharide (LPS, bacterial), anti-CD3 (antibody) and a version of the prominent SARS-CoV-2 viral surface molecule, Spike Glycoprotein, were individually sufficient to induce IL-6 and multiple chemokines in mice. They failed to upregulate the TH1 inducer cytokine Osteopontin, and the pathophysiologic triggers actually suppressed the PMA-induced Osteopontin secretion from monocytic cells. Osteopontin administration partially reversed the chemokine elevation, more effectively so in a mouse strain with TH1 bias. Corroboration was obtained from the inverse correlation in the levels of IL-6 and Osteopontin in plasma samples from acute COVID-19 patients. We hypothesize that the inhibition of Osteopontin by SARS-CoV-2 Spike Glycoprotein or LPS represents an immune evasion mechanism employed by the pathogens of origin. The ensuing dysfunctional inflammatory response promotes a vicious cycle of amplification, resulting in a cytokine storm.

Diagnosing Fracture-Related Infections: Where Are We Now?

Accurate diagnosis of fracture-related infection (FRI) is critical for preventing poor outcomes such as loss of function or amputation. Due to the multiple variables associated with FRI, however, accurate diagnosis is challenging and complicated by a lack of standardized diagnostic criteria. Limitations with the current gold standard for diagnosis, which is routine microbiology culture, further complicate the diagnostic and management process. Efforts to optimize the process rely on a foundation of data derived from prosthetic joint infections (PJI), but differences in PJI and FRI make it clear that unique approaches for these distinct infections are required. A more concerted effort focusing on FRI has dominated more recent investigations and publications leading to a consensus definition by the American Orthopedics (AO) Foundation and the European Bone and Joint Infection Society (EBJIS). This has the potential to better standardize the diagnostic process, which will not only improve patient care but also facilitate more robust and reproducible research related to the diagnosis and management of FRI. The purpose of this minireview is to explore the consensus definition, describe the foundation of data supporting current FRI diagnostic techniques, and identify pathways for optimization of clinical microbiology-based strategies and data.

Updates in Laboratory Diagnostics for Invasive Fungal Infections.

Appropriate diagnosis of invasive fungal infections (IFIs) is critical due to the high rates of morbidity and mortality, as well as the substantial economic burden, associated with the management of these diseases. The recognition of IFI and differentiation from other infections with similar clinical presentations can be challenging, which can lead to diagnostic error that not only has an impact on individual patient health outcomes but also on antimicrobial drug usage and the growing threat of antimicrobial resistance in bacteria. Therefore, there is a significant need for improved stewardship related to diagnostic testing for and treatment of IFIs. The purpose of this review is to highlight recent advances related to current fungal diagnostics, as well as explore some of the most innovative technology that has emerged with the potential to shift the paradigm of clinical mycology. In general, this review will discuss research related to enhanced fungal culture utilization and identification techniques, expanded applications of fungal antigen testing, and recently developed molecular assays and other novel nonculture fungal diagnostic approaches. Specifically, the application of mass spectrometry, novel glycobiomarker detection, and detection of fungal-specific volatile organic compounds will be reviewed, along with other key updates, to provide the reader with an updated review that extends beyond the basics of IFI laboratory diagnostics. Where appropriate, the reader will be directed to more comprehensive reviews of certain aspects of clinical mycology laboratory testing to provide a broader context for the critical consideration of these updates.

Molecular Diagnostic Testing for Aspergillus.

The direct detection of Aspergillus nucleic acid in clinical specimens has the potential to improve the diagnosis of aspergillosis by offering more rapid and sensitive identification of invasive infections than is possible with traditional techniques, such as culture or histopathology. Molecular tests for Aspergillus have been limited historically by lack of standardization and variable sensitivities and specificities. Recent efforts have been directed at addressing these limitations and optimizing assay performance using a variety of specimen types. This review provides a summary of standardization efforts and outlines the complexities of molecular testing for Aspergillus in clinical mycology.

Cost-Effectiveness Analysis of Multiplex PCR with Magnetic Resonance Detection versus Empiric or Blood Culture-Directed Therapy for Management of Suspected Candidemia.

Candida bloodstream infections (BSI) are associated with significant morbidity, mortality, and increased health care costs. Early treatment is essential, because delayed therapy detrimentally impacts clinical outcomes. The FDA recently approved the first culture-independent direct molecular detection method for Candida BSIs (T2Candida). The speed and sensitivity of this assay give it the potential to improve patient care, but the reagents and instrumentation are expensive. We used an analytic decision tree model to compare the cost-effectiveness of T2Candida-directed antifungal therapy (T2DT) to that of either empirical therapy (ET) or blood culture-directed therapy (BCDT). The costs included those of T2Candida testing, antifungal treatment, and hospital length of stay. The effectiveness measure was survival status at hospital discharge. T2DT was less costly and more effective than BCDT but was less costly and less effective than ET with an echinocandin (incremental cost-effectiveness ratio, $111,084 per additional survivor). One-way sensitivity analyses demonstrated that the cost-effectiveness of T2DT was highly dependent on Candida BSI prevalence and the cost of antifungal therapy and T2Candida test reagents. The use of T2DT reduced the number of unnecessarily treated patients by 98% relative to that with ET. Reduced drug exposure might lessen the possibility of drug-related adverse events and may also prevent the development of antifungal resistance or emergence of drug-resistant Candida species. The greatest benefit of T2Candida appears to be the ability to confidently withhold or stop empirical antifungal therapy in low-to-moderate-risk patients who are unlikely to benefit from treatment.

Effects of a defective endoplasmic reticulum-associated degradation pathway on the stress response, virulence, and antifungal drug susceptibility of the mold pathogen Aspergillus fumigatus.

Proteins that are destined for release outside the eukaryotic cell, insertion into the plasma membrane, or delivery to intracellular organelles are processed and folded in the endoplasmic reticulum (ER). An imbalance between the level of nascent proteins entering the ER and the organelle's ability to manage that load results in the accumulation of unfolded proteins. Terminally unfolded proteins are disposed of by ER-associated degradation (ERAD), a pathway that transports the aberrant proteins across the ER membrane into the cytosol for proteasomal degradation. The ERAD pathway was targeted in the mold pathogen Aspergillus fumigatus by deleting the hrdA gene, encoding the A. fumigatus ortholog of Hrd1, the E3 ubiquitin ligase previously shown to contribute to ERAD in other species. Loss of HrdA was associated with impaired degradation of a folding-defective ERAD substrate, CPY*, as well as activation of the unfolded-protein response (UPR). The ΔhrdA mutant showed resistance to voriconazole and reduced thermotolerance but was otherwise unaffected by a variety of environmental stressors. A double-deletion mutant deficient in both HrdA and another component of the same ERAD complex, DerA, was defective in secretion and showed hypersensitivity to ER, thermal, and cell wall stress. However, the ΔhrdA ΔderA mutant remained virulent in mouse and insect infection models. These data demonstrate that HrdA and DerA support complementary ERAD functions that promote survival under conditions of ER stress but are dispensable for virulence in the host environment.

Ambulatory Long Block: A Model of Precision Education and Assessment for Internal Medicine Residents.

ABSTRACT: High-quality precision education (PE) aims to enhance outcomes for learners and society by incorporating longitudinal data and analytics to shape personalized learning strategies. However, existing educational data collection methods often suffer from fragmentation, leading to gaps in understanding learner and program performance. In this article, the authors present a novel approach to PE at the University of Cincinnati, focusing on the Ambulatory Long Block, a year-long continuous ambulatory group-practice experience. Over the last 17 years, the Ambulatory Long Block has evolved into a sophisticated data collection and analysis system that integrates feedback from various stakeholders, as well as learner self-assessment, electronic health record utilization information, and clinical throughput metrics. The authors detail their approach to data prioritization, collection, analysis, visualization, and feedback, providing a practical example of PE in action. This model has been associated with improvements in both learner performance and patient care outcomes. The authors also highlight the potential for real-time data review through automation and emphasize the importance of collaboration in advancing PE. Generalizable principles include designing learning environments with continuity as a central feature, gathering both quantitative and qualitative performance data from interprofessional assessors, using this information to supplement traditional workplace-based assessments, and pairing it with self-assessments. The authors advocate for criterion referencing over normative comparisons, using user-friendly data visualizations, and employing tailored coaching strategies for individual learners. The Ambulatory Long Block model underscores the potential of PE to drive improvements in medical education and health care outcomes.

HacA-independent functions of the ER stress sensor IreA synergize with the canonical UPR to influence virulence traits in Aspergillus fumigatus.

Endoplasmic reticulum (ER) stress is a condition in which the protein folding capacity of the ER becomes overwhelmed by an increased demand for secretion or by exposure to compounds that disrupt ER homeostasis. In yeast and other fungi, the accumulation of unfolded proteins is detected by the ER-transmembrane sensor IreA/Ire1, which responds by cleaving an intron from the downstream cytoplasmic mRNA HacA/Hac1, allowing for the translation of a transcription factor that coordinates a series of adaptive responses that are collectively known as the unfolded protein response (UPR). Here, we examined the contribution of IreA to growth and virulence in the human fungal pathogen Aspergillus fumigatus. Gene expression profiling revealed that A. fumigatus IreA signals predominantly through the canonical IreA-HacA pathway under conditions of severe ER stress. However, in the absence of ER stress IreA controls dual signaling circuits that are both HacA-dependent and HacA-independent. We found that a ΔireA mutant was avirulent in a mouse model of invasive aspergillosis, which contrasts the partial virulence of a ΔhacA mutant, suggesting that IreA contributes to pathogenesis independently of HacA. In support of this conclusion, we found that the ΔireA mutant had more severe defects in the expression of multiple virulence-related traits relative to ΔhacA, including reduced thermotolerance, decreased nutritional versatility, impaired growth under hypoxia, altered cell wall and membrane composition, and increased susceptibility to azole antifungals. In addition, full or partial virulence could be restored to the ΔireA mutant by complementation with either the induced form of the hacA mRNA, hacA(i), or an ireA deletion mutant that was incapable of processing the hacA mRNA, ireA(Δ10). Together, these findings demonstrate that IreA has both HacA-dependent and HacA-independent functions that contribute to the expression of traits that are essential for virulence in A. fumigatus.

An evaluation of the impact and costs of three strategies used to recruit acutely unwell young children to a randomised controlled trial in primary care.

BACKGROUND: Recruitment to primary care trials, particularly those involving young children, is known to be difficult. There are limited data available to inform researchers about the effectiveness of different trial recruitment strategies and their associated costs. PURPOSE: To describe, evaluate, and investigate the costs of three strategies for recruiting febrile children to a community-based randomised trial of antipyretics. METHODS: The three recruitment strategies used in the trial were termed as follows: (1) 'local', where paediatric research nurses stationed in primary care sites invited parents of children to participate; (2) 'remote', where clinicians at primary care sites faxed details of potentially eligible children to the trial office; and (3) 'community', where parents, responding to trial publicity, directly contacted the trial office when their child was unwell. RESULTS: Recruitment rates increased in response to the sequential introduction of three recruitment strategies, which were supplemented by additional recruiting staff, flexible staff work patterns, and improved clinician reimbursement schemes. The three strategies yielded different randomisation rates. They also appeared to be interdependent and highly effective together. Strategy-specific costs varied from £297 to £857 per randomised participant and represented approximately 10% of the total trial budget. LIMITATIONS: Because the recruitment strategies were implemented sequentially, it was difficult to measure their independent effects. The cost analysis was performed retrospectively. CONCLUSIONS: Trial recruiter expertise and deployment of several interdependent, illness-specific strategies were key factors in achieving rapid recruitment of young children to a community-based randomised controlled trial (RCT). The 'remote' recruitment strategy was shown to be more cost-effective compared to 'community' and 'local' strategies in the context of this trial. Future trialists should report recruitment costs to facilitate a transparent evaluation of recruitment strategy cost-effectiveness.

The TARGET cohort study protocol: a prospective primary care cohort study to derive and validate a clinical prediction rule to improve the targeting of antibiotics in children with respiratory tract illnesses.

BACKGROUND: Children with respiratory tract infections are the single most frequent patient group to make use of primary care health care resources. The use of antibiotics remains highly prevalent in young children, but can lead to antimicrobial resistance as well as reinforcing the idea that parents should re-consult for similar symptoms. One of the main drivers of indiscriminate antimicrobial use is the lack of evidence for, and therefore uncertainty regarding, which children are at risk of poor outcome. This paper describes the protocol for the TARGET cohort study, which aims to derive and validate a clinical prediction rule to identify children presenting to primary care with respiratory tract infections who are at risk of hospitalisation. METHODS/DESIGN: The TARGET cohort study is a large, multicentre prospective observational study aiming to recruit 8,300 children aged ≥3 months and <16 years presenting to primary care with a cough and respiratory tract infection symptoms from 4 study centres (Bristol, London, Oxford and Southampton). Following informed consent, symptoms, signs and demographics will be measured. In around a quarter of children from the Bristol centre, a single sweep, dual bacterial-viral throat swab will be taken and parents asked to complete a symptom diary until the child is completely well or for 28 days, whichever is sooner. A review of medical notes including clinical history, re-consultation and hospitalisations will be undertaken. Multivariable logistic regression will be used to identify the independent clinical predictors of hospitalisation as well as the prognostic significance of upper respiratory tract microbes. The clinical prediction rule will be internally validated using various methods including bootstrapping. DISCUSSION: The clinical prediction rule for hospitalisation has the potential to help identify a small group of children for hospitalisation and a much larger group where hospitalisation is very unlikely and antibiotic prescribing would be less warranted. This study will also be the largest natural history study to date of children presenting to primary care with acute cough and respiratory tract infections, and will provide important information on symptom duration, re-consultations and the microbiology of the upper respiratory tract.

The low sensitivity of direct smears limit the utility of intraoperative gram stains for predicting culture-positivity in acute surgical settings.

The role of intraoperative Gram stains in acute surgery decision-making is unclear. Our retrospective chart review of microbiology results for specimens submitted by acute surgery attendings showed Gram stain performs with a sensitivity ranging from 18% to 65% compared to culture, depending on organism type, thus limiting its utility.

Immune and ionic mechanisms mediating the effect of dexamethasone in severe COVID-19.

Introduction: Severe COVID-19 is characterized by cytokine storm, an excessive production of proinflammatory cytokines that contributes to acute lung damage and death. Dexamethasone is routinely used to treat severe COVID-19 and has been shown to reduce patient mortality. However, the mechanisms underlying the beneficial effects of dexamethasone are poorly understood. Methods: We conducted transcriptomic analysis of peripheral blood mononuclear cells (PBMCs) from COVID-19 patients with mild disease, and patients with severe COVID-19 with and without dexamethasone treatment. We then treated healthy donor PBMCs in vitro with dexamethasone and investigated the effects of dexamethasone treatment ion channel abundance (by RT-qPCR and flow cytometry) and function (by electrophysiology, Ca2+ influx measurements and cytokine release) in T cells. Results: We observed that dexamethasone treatment in severe COVID-19 inhibited pro-inflammatory and immune exhaustion pathways, circulating cytotoxic and Th1 cells, interferon (IFN) signaling, genes involved in cytokine storm, and Ca2+ signaling. Ca2+ influx is regulated by Kv1.3 potassium channels, but their role in COVID-19 pathogenesis remains elusive. Kv1.3 mRNA was increased in PBMCs of severe COVID-19 patients, and was significantly reduced in the dexamethasone-treated group. In agreement with these findings, in vitro treatment of healthy donor PBMCs with dexamethasone reduced Kv1.3 abundance in T cells and CD56dimNK cells. Furthermore, functional studies showed that dexamethasone treatment significantly reduced Kv1.3 activity, Ca2+ influx and IFN-g production in T cells. Conclusion: Our findings suggest that dexamethasone attenuates inflammatory cytokine release via Kv1.3 suppression, and this mechanism contributes to dexamethasone-mediated immunosuppression in severe COVID-19.

Clinical Utility of the Signal-to-Cutoff Ratio of Reactive HIV Antigen/Antibody Screening Tests in Guiding Emergency Physician Management.

BACKGROUND: The signal-to-cutoff (S/CO) ratio of the HIV antigen/antibody test may help immediately to differentiate true-positive results from false-positive results, which may be particularly useful in time-sensitive circumstances, such as when providing emergency department (ED) care. SETTING: Seven US EDs with HIV screening programs using HIV antigen/antibody assays. METHODS: This cross-sectional study of existing data correlated S/CO ratios with confirmed HIV status. Test characteristics at predetermined S/CO ratios and the S/CO ratio with the best performance by receiver operator characteristic (ROC) curve were calculated. RESULTS: Of 1035 patients with a reactive HIV antigen/antibody test, 232 (22.4%) were confirmed HIV-negative and 803 (77.6%) were confirmed HIV-positive. Of the 803 patients, 713 (88.8%) experienced chronic infections and 90 (11.2%) experienced acute infections. S/CO ratios were greater for HIV-positive (median 539.2) than for HIV-negative patients (median 1.93) (P < 0.001) and lower for acute infection (median 22.8) than for chronic infection (median 605.7) (P < 0.001). All patients with an S/CO ratio < 1.58 (n = 93) were HIV-negative (NPV 100%), and nearly all with an S/CO ≥ 20.7 (n = 760) (optimal level by ROC analysis) were HIV-positive (PPV 98.6%). Of patients with S/CO values between 1.58 and 20.7 (n = 182), 29.7% were HIV-positive. CONCLUSIONS: The S/CO ratio may be used in real time to classify most ED patients as almost certain to be either HIV-positive or HIV-negative long before nucleic acid confirmatory testing is available. When combined with clinical judgment, this could guide preliminary result disclosure and management.

Safety, Pharmacokinetics, and Pharmacodynamics of Trazpiroben (TAK-906), a Novel Selective D2 /D3 Receptor Antagonist: A Phase 1 Randomized, Placebo-Controlled Single- and Multiple-Dose Escalation Study in Healthy Participants.

Gastroparesis is a chronic neuromuscular disorder of the upper gastrointestinal tract in which episodic exacerbation can lead to frequent hospitalizations and severe disability. Dopamine D2 /D3 receptor antagonists have been used to treat patients with gastroparesis with some efficacy; however, their chronic use is limited owing to associated central nervous system (CNS) or cardiovascular safety concerns. Trazpiroben (TAK-906) is a dopamine D2 /D3 receptor antagonist under development for the long-term treatment of gastroparesis. Preclinical studies in rat and dog have shown trazpiroben to have minimal brain penetration and low affinity for the human ether-à-go-go-related gene (hERG) potassium channel (IC50 ,  15.6 µM), thereby reducing the risk of the CNS and cardiovascular adverse effects seen with other dopamine D2 /D3 receptor antagonists. This phase 1 trial evaluated the safety, pharmacokinetics, and pharmacodynamics of trazpiroben in healthy participants. Trazpiroben was rapidly absorbed and eliminated (Tmax , ∼1.1 hours; t1/2 , 4-11 hours) after administration of single (5-300 mg) and multiple (50 or 100 mg) doses. Receptor target engagement was confirmed for all doses, as indicated by an increase in serum prolactin levels compared with placebo (mean prolactin Cmax , 134.3 ng/mL after administration of trazpiroben 10 mg vs 16.1 ng/mL with placebo). Therapeutically relevant single and multiple doses of trazpiroben were well tolerated in healthy participants, and no clinically meaningful cardiovascular adverse effects were observed across the whole dose range. These data support the further development of trazpiroben for the treatment of gastroparesis.

Take Your Best Shot: Which SARS-CoV-2 Vaccine Should I Get?

Background. Three vaccines against SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) have now received emergency use authorization by the US Food and Drug Administration. Patients may have the opportunity to make a choice about which vaccine they prefer to receive. Vaccine hesitancy is a hurdle to the development of widespread immunity, with many patients struggling to decide whether to get vaccinated at all. Objective. Develop a decision model exploring the question, "Should I get vaccinated with mRNA or adenovirus vector vaccine (AVV) if either is available now?"Design. Markov state transition model with lifetime time horizon. Data Sources. MEDLINE searches, bibliographies from relevant English-language articles. Setting. United States, ambulatory clinical setting. Participants. Previously uninfected, nonimmunized adults in the United States. Interventions. 1) Do Not Vaccinate, 2) Vaccination with mRNA Vaccine, 3) Vaccination with Adenovirus Vector Vaccine. Main Measures. Quality-adjusted life years (QALYs). Key Results. Base case-for a healthy 65-year-old patient, both vaccines yield virtually equivalent results (difference of 0.0028 QALYs). In sensitivity analyses, receiving the AVV is preferred if the short-term morbidity associated with each vaccine dose exceeds 1.8 days. Both vaccines afford an even greater benefit compared with Do Not Vaccinate if the pandemic is in a surge phase with a rising incidence of infection or if the current 7-day incidence is greater than the base case estimate of 105 cases per 100,000. Conclusions. Preferred vaccination strategies change under differing assumptions, but differences in outcomes are negligible. The best advice for patients is to get vaccinated against COVID-19 disease with whatever vaccine is available first. Providing mRNA vaccine to the remaining eligible US population would result in an aggregate gain of 3.92 million QALYs.